Thread by @julnicolas

Excited to share our work on subcutaneous administration of hydrophobic, vesicant anticancer drugs via water-soluble polymer prodrugs out in @J_A_C_S Wonderful team effort! @ERC_Research @UnivParisSaclay @CNRS @INC_CNRS @CNRSIdFSud @Pharma_UPSaclay doi.org/10.1021/jacs.2…
🧵1/n

👉 Chemotherapy is almost exclusively administered intravenously (IV) which has serious limitations:
➡️Patient discomfort (central route🩸, catheter failure…)
➡️Frequent hospital stays🏥, trained staff🩺👨‍⚕️needed…
➡️Costly (and cost will 📈 as new cancer cases will 📈)
🧵2/n

What about other administration routes?
➡️Oral route 💊: very restrictive. Low and variable bioavailability. Chemo requires precise dosing.
➡️Subcutaneous (SC) route 💉: not possible for vesicant/irritant drugs because of skin ulceration 🚨 and even necrosis ☠️
🧵3/n

SC administration has many benefits vs. IV:
✅More comfortable for the patient (less invasive, easy to perform) 💉
✅No hospital stay
✅Less costly
✅Towards home chemotherapy and self-administration?
🧵4/n

What about #nanomedicine #nanoparticles #liposomes for SC delivery?
➡️No example applied to vesisant/irritant drugs, and there are many of them (taxanes, vinca alkaloids, Dox, Gem, Pt-based...)
📋Only 9 (!) anticancer drugs are approved for SC delivery, all non-irritant
🧵5/n

💡SC administration of water-soluble polymer prodrugs (= drug-polymer conjugation)
Our system:
▪️ Drug: Paclitaxel (Ptx). Hydrophobic, vesicant anticancer drug➡️Taxol
▪️ Polymer: Polyacrylamide (PAAm). Super hydrophilic polymer, biocompatible (wrinkle filler⤵️), stealth
🧵6/n

Ptx-PAAm prodrugs were synthesized by the drug-initiated method:
✅Few steps, high yields
✅Easy work up (unreacted AAm to be removed only)
✅Adjusting the PAAm chain length➡️water-solubility
✅Changing the nature of the Ptx-PAAm linker➡️tuning Ptx release
✅Scalable
🧵7/n

We synthesized well-defined Ptx-PAAm prodrugs by RAFT polymerization:
▪️ Mn ~20 kDa to achieve water-solubility
▪️ 3 different linkers tested (carbonate, ester, diglycolate) to tune Ptx release kinetics
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We then did a preclinical development of the prodrugs (injectab, Ptx release, MTT, systemic & local tox, PK, biodis📊, anticancer efficacy📈)

In🐭vs Taxol:
✅No local tox (histo), much higher MTD
✅Cmax / 15-114
✅Ptx-ester-PAAm: stealth (t1/2 = 14 h) & 84% bioavailab.
🧵9/n

What about anticancer efficacy❓
Taxol IV vs Ptx-PAAm SC:

✅Same Ptx dose => same efficacy
➡️Successful switch from Taxol IV to Ptx SC under the form of polymer prodrugs🥳

✅x3 Ptx dose (cf MTD) => higher efficacy
➡️Ptx-based polymer prodrugs SC outperfom Taxol IV 🥳
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So what’s next⁉️
Startup company @Imescia_ created w/ @NTsapis, @AlexBordat & @tanguyboissenot
2 goals:
1⃣Indus. collab. w/ pharma companies to deliver their own (poorly soluble) drugs via our approach
2⃣Raise funds (2.5 M€ needed🙏) to start a clinical trial in humans in 2024

Last but not least, many people to thank in this exciting (ongoing) journey:
▪️ co-authors🙏 incl. @NTsapis @AlexBordat @tanguyboissenot @EbrahimNada09 @PietersGregory1
▪️ @cnrs @cnrsinnovation @Brahim_Sennane @julesmeunier @SATTSaclay @ParisBiotech @Pharma_UPSaclay
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▪️ @umr8612 @WILCO_startup @LaFrenchTech @AstraZenecaFR @Bpifrance @UnivParisSaclay @ERC_Research @CEAParisSaclay #LabOniris @laliguecancer
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